GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones

• Published in: The Journal of physiology Vol. 548; no. 2; pp. 373 - 382
• Main Authors: Baker, Mark D, Chandra, Sonia Y, Ding, Yanning, Waxman, Stephen G, Wood, John N
• Format: Journal Article
• Language: English
• Published: England The Physiological Society 15-04-2003; Blackwell Science Inc
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Algorithms; Animals; Electrophysiology; Excitatory Postsynaptic Potentials - drug effects; GTP-Binding Proteins - physiology; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacology; Guanosine Triphosphate - pharmacology; Mice; NAV1.9 Voltage-Gated Sodium Channel; Neurons, Afferent - drug effects; Neurons, Afferent - ultrastructure; Neuropeptides - agonists; Neuropeptides - drug effects; Neuropeptides - metabolism; Original; Patch-Clamp Techniques; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Sodium Channel Agonists; Sodium Channel Blockers - pharmacology; Sodium Channels - drug effects; Sodium Channels - metabolism; Tetrodotoxin - pharmacology; Up-Regulation - drug effects
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2003.039131

Peripheral pain thresholds are regulated by the actions of inflammatory mediators. Some act through G-protein-coupled receptors
on voltage-gated sodium channels. We have found that a low-threshold, persistent tetrodotoxin-resistant Na + current, attributed to Na V 1.9, is upregulated by GTP and its non-hydrolysable analogue GTP-γ-S, but not by GDP. Inclusion of GTP-γ-S (500 μ m ) in the internal solution led to an increase in maximal current amplitude of > 300 % within 5 min. In current clamp, upregulation
of persistent current was associated with a more negative threshold for action potential induction (by 15–16 mV) assessed
from a holding potential of −90 mV. This was not seen in neurones without the low-threshold current or with internal GDP ( P < 0.001). In addition, persistent current upregulation depolarized neurones. At −60 mV, internal GTP-γ-S led to the generation
of spontaneous activity in initially silent neurones only when persistent current was upregulated. These findings suggest
that regulation of the persistent current has important consequences for nociceptor excitability.